Search

Abstract Background While asthma exacerbations remain a major challenge in patient management, few animal models exist to explore the underlying mechanisms. Here, we established an animal model of asthma that can be used to study pathophysiological mechanisms and therapeutic strategies on asthma exacerbation. Methods Female BALB/c mice were sensitized and exposed to PBS or Dermatophagoides pteronyssinus (DerP) extract for 11 weeks. Asthmatic phenotype was assessed through lung inflammation, bronchial hyperresponsiveness and bronchial smooth muscle remodeling. Asthmatic and control mice were exposed once or three times to poly(I:C) to simulate virus-induced inflammation. Results Fourteen days after exposure to DerP, asthmatic mice showed resolution of inflammation with sustained bronchial hyperresponsiveness and bronchial smooth muscle remodeling compared to control. At this stage, when mice were subjected to a single exposure to poly(I:C), control and asthmatic mice were characterized by a significant increase in neutrophilic inflammation and bronchial hyperresponsiveness. When mice were repeatedly exposed to poly(I:C), control mice showed a significant decrease in neutrophilic inflammation and bronchial hyperresponsiveness, while asthmatic mice experienced worsening of these outcomes. Conclusions This observational study report an asthmatic mouse model that can undergo exacerbation after repeated exposure to poly(I:C). Our findings on pulmonary adaptation in control mice may also pave the way for further research into the mechanism of adaptation that may be impaired in asthma and raise the question of whether asthma exacerbation may be a loss of adaptation.

Abstract Personality is a central concept and a cross-domain explanatory factor in psychology to characterize and differentiate individuals. Surprisingly, among the many studies on oculomotor behavior, only a few have investigated how personality influences the exploration of a visual stimulus. Due to the limited number of existing studies, it is still uncertain if markers of personality in eye movements are always observable in eye movements across various exploration contexts. Here, introducing a novel concept of gaze-based signatures of personality, we used visual exploration metrics to detect personality signatures across various exploration contexts (visual search and free-viewing on images and webpages) in 91 participants. Personality data were collected as in the reference paper that validated the French version of the Big Five Inventory. Linear regression analyses demonstrated that while Extraversion and Openness to Experience did not correlate with any particular exploration metric, the other three traits–Conscientiousness, Agreeableness, and Neuroticism–correlated robustly with all exploration metrics in different visual exploration contexts. Our study provides evidence for the capture of the gaze-based signature of personality from very brief eye movement recordings.

Background: The major drivers of carbon dioxide (CO2eq) emissions of external beam radiation therapy (EBRT) are not well known and limit our ability to initiate mitigation strategies. Material and methods: We describe the carbon footprint of four typical centers. We explore direct EBRT associated factors such as the impact of fractionation and use of MRI-LINAC, as well as indirect factors (e.g. patient rides). Treatment strategy related CO2eq emissions are included in a health technology assessment analysis that takes into account CO2eq emissions. Results: A typical EBRT treatment emits from 185 kgCO2eq to 2066 kgCO2eq. CO2eq emissions are mostly driven by (i) accelerator acquisition and maintenance (37.8 %), (ii) patients and workers rides (32.7 %), (iii) drugs and medical devices (7.3 %), (iv) direct energy consumption (6.1 %), and (v) building and bunker construction (5.6 %) with a substantial heterogeneity among centers. Hypofractionation has a strong impact to mitigate emissions. MRI-LINAC is associated with a substantial increase in CO2eq emissions per fraction and requires ultra hypofractionation in 5 fractions to achieve a similar carbon footprint compared to 20 fractions treatment schemes. The expected limited small increase in toxicities due to hypofractionation (when existing) are in the same range as avoided detrimental effects to future people’s health thanks to CO2eq mitigation. Conclusion: Carbon footprint of EBRT is not neglectable and could be mitigated. When safely feasible, hypofractionation is one of the main factors to decrease this impact. Taking into account CO2eq emissions has a substantial impact on the health technology assessment of EBRT, favoring hypofractionated regimens.

Abstract Background To date, almost no research on the psychosocial implications of albinism has been conducted in France and an exploration of albinism-related experiences could be beneficial, in order to better understand this condition. The aim of this study was to examine how French people with albinism and their parents live with and adapt to this condition in all the areas of their lives. Methods Semi-structured phone interviews were conducted with 9 parent-child dyads, each participating separately. Participants were recruited by convenience sampling, thanks to the combined efforts of a patient association (Genespoir) and professionals from the partner medical referral centers involved in the project. Dyads in which the individual with albinism had any comorbidity were excluded. The interviews were then transcribed and subjected to in-depth thematic analysis. Two codebooks were constructed in a mirrored process: one for people with albinism; the other for their parents. They were finally merged at the end of the coding step. Results Four main categories were identified: personal perceptions and social representations of albinism, difficulties and obstacles encountered by people with albinism, resources and facilitators, and the importance of parent-child functioning. The results indicated that experiences of stigmatization during childhood and adolescence are common and that people with albinism face challenges in adapting to certain obstacles related to their visual impairments (VI) (e.g., inability to drive a car; eye strain...). Parents emerged as one, if not as the main, source of support for people with albinism throughout their development. Although external support systems exist to assist them in various aspects of their lives, some of them primarily rely on their own personal resources to cope. Conclusions This research highlights the importance of a systemic and transdisciplinary approach to make sure families receive the support that best meets their needs.

Abstract Tilapia Lake Virus (TiLV), a recently discovered pathogen of tilapia fish, belongs to the Amnoonviridae family from the Articulavirales order. Its ten genome segments have characteristic conserved ends and encode proteins with no known homologues, apart from the segment 1, which encodes an orthomyxo-like RNA-dependent-RNA polymerase core subunit. Here we show that segments 1–3 encode respectively the PB1, PB2 and PA-like subunits of an active heterotrimeric polymerase that maintains all domains found in the distantly related influenza polymerase, despite an unprecedented overall size reduction of 40%. Multiple high-resolution cryo-EM structures of TiLV polymerase in pre-initiation, initiation and active elongation states, show how it binds the vRNA and cRNA promoters and performs RNA synthesis, with both transcriptase and replicase configurations being characterised. However, the highly truncated endonuclease-like domain appears inactive and the putative cap-binding domain is autoinhibited, emphasising that many functional aspects of TiLV polymerase remain to be elucidated.

Albinism is a genetically heterogeneous disease in which 21 genes are known so far. Its inheritance mode is autosomal recessive except for one X-linked form. The molecular analysis of exonic sequences of these genes allows for about a 70% diagnostic rate. About half (15%) of the unsolved cases are heterozygous for one pathogenic or probably pathogenic variant. Assuming that the missing variant may be located in non-coding regions, we performed sequencing for 122 such heterozygous patients of either the whole genome (27 patients) or our NGS panel (95 patients) that includes, in addition to all exons of the 21 genes, the introns and flanking sequences of five genes, TYR, OCA2, SLC45A2, GPR143 and HPS1. Rare variants (MAF < 0.01) in trans to the first variant were tested by RT-PCR and/or minigene assay. Of the 14 variants tested, nine caused either exon skipping or the inclusion of a pseudoexon, allowing for the diagnosis of 11 patients. This represents 9.8% (12/122) supplementary diagnosis for formerly unsolved patients and 75% (12/16) of those in whom the candidate variant was in trans to the first variant. Of note, one missense variant was demonstrated to cause skipping of the exon in which it is located, thus shedding new light on its pathogenic mechanism. Searching for non-coding variants and testing them for an effect on RNA splicing is warranted in order to increase the diagnostic rate.

Abstract Introduction Keratoconus has a significant impact on patients’ quality of life (QoL), from diagnosis to the advanced stages of the disease. The aim of this research was to identify domains of QoL affected by this disease and its treatment. Methods Phone interviews were conducted using a semi-structured interview guide, with patients with keratoconus stratified according to their current treatment. A board of keratoconus experts helped identify the guide’s main themes. Results Thirty-five patients (rigid contact lenses, n = 9; cross-linking, n = 9; corneal ring implants, n = 8; and corneal transplantation, n = 9) were interviewed by qualitative researchers. Phone interviews revealed several QoL domains affected by the disease and its treatments: “psychological”, “social life”, “professional life”, “financial costs” and “student life”. All domains were impacted, independently of the treatment history. Few differences were found between treatment regimens and keratoconus stages. Qualitative analysis enabled the development of a conceptual framework based on Wilson and Cleary’s model for patient outcomes common to all patients. This conceptual model describes the relationship between patients’ characteristics, their symptoms, their environment, their functional visual impairment and the impact on their QoL. Conclusions These qualitative findings supported the generation of a questionnaire to evaluate the impact of keratoconus and its treatment on patients’ QoL. Cognitive debriefings confirmed its content validity. The questionnaire is applicable for all stages of keratoconus and treatments and may help tracking change over time in regular clinical settings. Psychometric validation is yet to be performed before its use in research and clinical practices.

As the COVID-19 pandemic unfolded, community pharmacies adapted rapidly to broaden and adjust the services they were providing to patients, while coping with severe pressure on supply chains and constrained social interactions. This study investigates whether these events had an impact on the medication incidents reported by pharmacists. Results indicate that Canadian pharmacies were able to sustain such stress while maintaining comparable safety levels. At the same time, it appears that some risk factors that were either ignored or not meaningful in the past started to be reported, suggesting that community pharmacists are now aware of a larger set of contributing factors that can lead to medication incidents, notably for medication incidents that can lead to harm.

PIEZO proteins are large, mechanically-activated trimeric ion channels. Here the authors report a light-gated mouse PIEZO1 channel, mOP1, whereby an azobenzene-based photoswitch covalently localised at the extracellular apex of a transmembrane helix, rapidly triggers channel gating on light irradiation.

In recent years, policymakers worldwide have emphasized innovative solutions for urban challenges, guided by initiatives like the UN’s Sustainable Development Goals and the European Green Deal. Nature-based solutions (NBS) play a crucial role in addressing climate issues and improving urban well-being. With urban areas witnessing a surge in NBS demand due to their dense populations, initiatives like green wall technologies, such as Living Walls (LW), are becoming more prevalent. However, integrating vegetation onto buildings presents complexities requiring structured support. This research aims to establish a robust foundation for LW design by combining existing standards, exploring current approaches, and pushing architectural and structural practices. It seeks to provide comprehensive guidelines for LW design to enhance efficacy, durability, and safety while preventing errors. Notably, existing global guidance lacks uniformity, necessitating a detailed European guide for LW design and maintenance. The methodology involves consolidating global guidelines and analysing current LW solutions to identify guidance gaps. Anticipated outcomes include foundational guidelines for architects and structural designers to improve LW processes, guiding further research and testing for advanced LW practices.

Brewer’s spent grain (BSG) is an undervalorized organic feedstock residue composed of fermentable macromolecules, such as proteins, starch, and residual soluble carbohydrates. It also contains at least 50% (as dry weight) of lignocellulose. Methane-arrested anaerobic digestion is one of the promising microbial technologies to valorize such complex organic feedstock into value-added metabolic intermediates, such as ethanol, H2, and short-chain carboxylates (SCC). Under specific fermentation conditions, these intermediates can be microbially transformed into medium-chain carboxylates through a chain elongation pathway. Medium-chain carboxylates are of great interest as they can be used as bio-based pesticides, food additives, or components of drug formulations. They can also be easily upgraded by classical organic chemistry into bio-based fuels and chemicals. This study investigates the production potential of medium-chain carboxylates driven by a mixed microbial culture in the presence of BSG as an organic substrate. Because the conversion of complex organic feedstock to medium-chain carboxylates is limited by the electron donor content, we assessed the supplementation of H2 in the headspace to improve the chain elongation yield and increase the production of medium-chain carboxylates. The supply of CO2 as a carbon source was tested as well. The additions of H2 alone, CO2 alone, and both H2 and CO2 were compared. The exogenous supply of H2 alone allowed CO2 produced during acidogenesis to be consumed and nearly doubled the medium-chain carboxylate production yield. The exogenous supply of CO2 alone inhibited the whole fermentation. The supplementation of both H2 and CO2 allowed a second elongation phase when the organic feedstock was exhausted, which increased the medium-chain carboxylate production by 285% compared to the N2 reference condition. Carbon- and electron-equivalent balances, and the stoichiometric ratio of 3 observed for the consumed H2/CO2, suggest an H2- and CO2-driven second elongation phase, converting SCC to medium-chain carboxylates without an organic electron donor. The thermodynamic assessment confirmed the feasibility of such elongation.

There is growing evidence linking hearing impairments and the deterioration of postural stability in older adults. To our knowledge, however, no study to date has investigated the effect of age-related hearing loss on the sensory reweighting process during postural control. In the absence of data, much is unknown about the possible mechanisms, both deleterious and compensatory, that could underly the deterioration of postural control following hearing loss in the elderly. The aim of this study was to empirically examine sensory reweighting for postural control in older adults with age-related hearing loss as compared to older adults with normal hearing. The center of pressure of all participants was recorded using a force platform and the modified clinical test of sensory interaction and balance protocol. The results suggest that individuals with age-related hearing loss displayed increased somatosensory reliance relative to normal hearing younger adults. This increased reliance on somatosensory input does not appear to be effective in mitigating the loss of postural control, probably due to the concomitant deterioration of tactile and proprioceptive sensitivity and acuity associated with aging. Beyond helping to further define the role of auditory perception in postural control, these results further the understanding of sensory-related mechanisms associated with postural instability in older adults.

We assessed the use of evidence-based practice (EBP) among pharmacists working in community pharmacies in France and the factors linked to this practice. During 3 months in 2018, an online survey was sent to over 7000 active pharmacists and posted on pharmacists’ social media sites. In total, 595 pharmacists completed the questionnaire. The responders were on average younger than the general population of community pharmacists. The 40-item questionnaire described four fictional clinical cases reflecting typical situations (conventional medicine and complementary and alternative medicine) encountered daily by community pharmacists. Multiple-choice responses were proposed and scored according to whether they reflected EBP. A high total score indicated behaviour in line with EBP. We observed 344/595 participants with a positive EBP score (57.8% [53.7–61.8%]). Univariate and multivariate analyses were used to evaluate factors that might explain adherence to EPB (the pharmacy’s characteristics, the pharmacist’s status, the mode of continuing education and sources of information). The majority relied on pharmaceutical industry and other biased and/or non-evidence-based sources, particularly concerning information on homeopathic products. The consultation of independent reviews, health agency recommendations and peer-reviewed scientific journals was associated with evidence-based decisions. In contrast, reliance on pharmaceutical industry documents, personal experience and informal handbooks was linked to lower EBP scores. The level of EBP use by French community pharmacists needs to be improved to ensure that good-quality, science-based advice is given to customers.

Abstract Background Long-term treatment adherence is a worldwide concern, with nonadherence resulting from a complex interplay of behaviors and health beliefs. Determining an individual’s risk of nonadherence and identifying the drivers of that risk are crucial for the development of successful interventions for improving adherence. Here, we describe the development of a new tool assessing a comprehensive set of characteristics predictive of patients’ treatment adherence based on the Social, Psychological, Usage and Rational (SPUR) adherence framework. Concepts from existing self-reporting tools of adherence-related behaviors were identified following a targeted MEDLINE literature review and a subset of these concepts were then selected for inclusion in the new tool. SPUR tool items, simultaneously generated in US English and in French, were tested iteratively through two rounds of cognitive interviews with US and French patients taking long-term treatments for chronic diseases. The pilot SPUR tool, resulting from the qualitative analysis of patients’ responses, was then adapted to other cultural settings (China and the UK) and subjected to further rounds of cognitive testing. Results The literature review identified 27 relevant instruments, from which 49 concepts were included in the SPUR tool (Social: 6, Psychological: 13, Usage: 11, Rational: 19). Feedback from US and French patients suffering from diabetes, multiple sclerosis, or breast cancer (n = 14 for the first round; n = 16 for the second round) indicated that the SPUR tool was well accepted and consistently understood. Minor modifications were implemented, resulting in the retention of 45 items (Social: 5, Psychological: 14, Usage: 10, Rational: 16). Results from the cognitive interviews conducted in China (15 patients per round suffering from diabetes, breast cancer or chronic obstructive pulmonary disease) and the UK (15 patients suffering from diabetes) confirmed the validity of the tool content, with no notable differences being identified across countries or chronic conditions. Conclusion Our qualitative analyses indicated that the pilot SPUR tool is a promising model that may help clinicians and health systems to predict patient treatment behavior. Further steps using quantitative methods are needed to confirm its predictive validity and other psychometric properties.

Human TRIAP1 (TP53-regulated inhibitor of apoptosis 1; also known as p53CSV for p53-inducible cell survival factor) is the homolog of yeast Mdm35, a well-known chaperone that interacts with the Ups/PRELI family proteins and participates in the intramitochondrial transfer of lipids for the synthesis of cardiolipin (CL) and phosphatidylethanolamine. Although recent reports indicate that TRIAP1 is a prosurvival factor abnormally overexpressed in various types of cancer, knowledge about its molecular and metabolic function in human cells is still elusive. It is therefore critical to understand the metabolic and proliferative advantages that TRIAP1 expression provides to cancer cells. Here, in a colorectal cancer cell model, we report that the expression of TRIAP1 supports cancer cell proliferation and tumorigenesis. Depletion of TRIAP1 perturbed the mitochondrial ultrastructure, without a major impact on CL levels and mitochondrial activity. TRIAP1 depletion caused extramitochondrial perturbations resulting in changes in the endoplasmic reticulum-dependent lipid homeostasis and induction of a p53-mediated stress response. Furthermore, we observed that TRIAP1 depletion conferred a robust p53-mediated resistance to the metabolic stress caused by glutamine deprivation. These findings highlight the importance of TRIAP1 in tumorigenesis and indicate that the loss of TRIAP1 has extramitochondrial consequences that could impact on the metabolic plasticity of cancer cells and their response to conditions of nutrient deprivation.

The phase transformation kinetics of Ti–6Al–4V alloy was studied during rapid heating using in-situ high energy synchrotron diffraction and in-situ electrical resistivity measurement for heating rates varying from 0.03 to 200 °C.s−1. The application of Rietveld refinement to high energy synchrotron data tracked the mass fraction, mean lattice parameters and Full Width at Half Maximum (FWHM). For increasing heating rates, results evidenced a shift in the dissolution of α to β phase temperature range from 600 °C for 0.25C.s−1 to 960 °C for 200 °C.s−1. A Continuous Heating Transformation diagram (CHT) was constructed demonstrating the effect of high heating rate. The result also demonstrated a much narrower temperature transformation range at high temperature. FWHM showed a time-dependent decrease of the stress level and/or chemical heterogeneity in the β phase before the start of the α phase dissolution. The mean lattice parameter evolution of β phase suggested that the α phase dissolution kinetics was diffusion controlled despite a heating rate reached of 200 °C.s−1, leading to chemical heterogeneities in the β phase.

Abstract Background MPS IIIA is a rare, degenerative pediatric genetic disease characterized by symptoms impacting cognition, mobility and behavior; the mean age of death is around 15 years of age. Currently, there are no approved therapies for MPS IIIA. Methods A two-year, multi-center, prospective, descriptive cohort study was conducted to document the natural history course of MPS IIIA. In the context of this study, semi-structured interviews were performed with parents of children at study entry and one year later. Interview transcripts were analyzed using thematic analysis methods to identity concepts of interest to children and parents, identify what factors impacted parents’ burden the most, and develop qualitatively-derived disease severity stages. Children were sorted into these stages according to the symptoms their parents described at the entry interview. This sorting was compared quantitatively to the sorting of children at baseline according to the child’s calendar age and their BSID development quotient (DQ). Results 22 parents in France, Germany, the Netherlands and the UK were interviewed. Children ranged in age from 28 to 105 months (mean 61.4 months). The conceptual models for children’s symptoms and impacts and parents’ impacts provided a detailed and comprehensive picture of what it is like for children of various ages and their parents to live with MPS IIIA. Four factors were identified as mediating the burden perceived by parents: state support, family support, time since diagnosis, and parent coping strategy. Four disease stages were developed, accounting for both the presence and the severity of MPS IIIA symptoms. The comparison of children’s sorting into these stages with the BSID DQ and the child’s calendar age showed strong statistical associations. Conclusions The findings of this qualitative research embedded in a natural history study add to the current understanding of MPS IIIA as a complex disease that impacts every aspect of the lives of children and their families. This study demonstrates the unique potential of mixed methods research in rare diseases to address some of the current limitations of more traditional quantitative approaches by providing an individualized, detailed understanding of the patient experience.

Recent investigation reports that certain electronic circuits operate with the unfamiliar negative group delay (NGD) function. It is fundamentally stated that the NGD circuits can be classified in different types. For example, we have the simplest ones as LP and HP NGD circuit types. So far, all the NGD studies are focused on simple type function. In step up of the research about the NGD electronic circuit engineering, this paper develops an original theory of electronic circuit topology operating with double NGD-type behavior. The study consists in the theorization of three-port circuit simultaneously generating LP and HP NGD function types. The proposed three-port innovative circuit under study is innovatively composed of resistive-capacitive (RC) network of Tee-shaped topology. Moreover, the LP and HP double-NGD circuit is a first order cell which does not contain any inductive component. The LP and HP NGD analyses of the Tee-topology is based on the 3-D S-matrix modelling. Analytical investigation based on classical circuit theory is elaborated to determine the S-matrix model from the equivalent admittance matrix. The identification of the double-NGD function is established from the LP- and HP-NGD canonical forms. Hence, the specific double-NGD characteristics are defined in function of the R and C elements constituting the three-port topology. To validate the developed double-NGD theory, a proof-of-concept (PoC) of SMD lumped component-based three-port circuit is designed, simulated, fabricated and tested. The calculated, simulated and measured results from the three-port circuit PoC prototype in very good agreement confirm the double-NGD behavior. The proposed innovative NGD three-port circuit design is useful in the future for the synchronization of signals propagating through multi-way communication system.

The cultural challenge of educating Haitian rehabilitation professionals was identified by a Canadian francophone university which collaborated in the implementation and organization of international internships. Ethical cross-border internationalization should ensure reciprocity for partners. With this as a central value and in a context of pedagogical resource scarcity in Haiti, an intercultural educational partnership involved Haitian and Canadian university students situated in their respective countries in a Problem-Based Learning (PBL) course. Teachers and students applied principles of decolonization of health pedagogy principles were applied by teacher and students throughout this cross-border virtual synchronous PBL course. The aim of this study was to determine the feasibility and to identify facilitators and obstacles to conducting a cross-border virtual synchronous PBL course and its perceived benefits in the development of professional competencies. Five Canadian students and five Haitian students, all volunteers, took part in a 3-week cross-border virtual synchronous PBL course. Deductive qualitative content analysis of the transcripts from a 120-minute focus group discussion held one week after the course and a logbook kept during the project was conducted. The criteria deemed important to successfully replicate this project relate to: 1) The attributes of the students and teachers involved; 2) pedagogical preparation activities; and 3) the use of multiple communication strategies and connectivity plans. In addition to the acquisition of course content not readily available in Haiti, the student interactions inherent in the PBL method supported the acquisition of competencies such as collaboration, communication, and change agent advocacy promoted by the Canadian association of occupational therapy which contribute greatly to strengthening the students' professional identity.

Hybrids are often considered evolutionary dead ends because they do not generate viable offspring. Here, the authors show that sterile yeast hybrids generate genetic diversity through meiotic-like recombination by aborting meiosis and return to asexual growth.

Abstract Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are two cancer-derived blood biomarkers that inform on patient prognosis and treatment efficacy in breast cancer. We prospectively evaluated the clinical validity of quantifying both CTCs (CellSearch) and ctDNA (targeted next-generation sequencing). Their combined value as prognostic and early monitoring markers was assessed in 198 HER2-negative metastatic breast cancer patients. All patients were included in the prospective multicenter UCBG study COMET (NCT01745757) and treated by first-line chemotherapy with weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline and before the second cycle of chemotherapy. At baseline, CTCs and ctDNA were respectively detected in 72 and 74% of patients and were moderately correlated (Kendall’s τ = 0.3). Only 26 (13%) patients had neither detectable ctDNA nor CTCs. Variants were most frequently observed in TP53 and PIK3CA genes. KMT2C/MLL3 variants detected in ctDNA were significantly associated with a lower CTC count, while the opposite trend was seen with GATA3 alterations. Both CTC and ctDNA levels at baseline and after four weeks of treatment were correlated with survival. For progression-free and overall survival, the best multivariate prognostic model included tumor subtype (triple negative vs other), grade (grade 3 vs other), ctDNA variant allele frequency (VAF) at baseline (per 10% increase), and CTC count at four weeks (≥5CTC/7.5 mL). Overall, this study demonstrates that CTCs and ctDNA have nonoverlapping detection profiles and complementary prognostic values in metastatic breast cancer patients. A comprehensive liquid-biopsy approach may involve simultaneous detection of ctDNA and CTCs.

Abstract Objective Despite the development of new biologic therapies, methotrexate (MTX) remains the preferred initial disease-modifying anti-rheumatic drug to treat rheumatoid arthritis (RA). Adherence to disease-modifying anti-rheumatic drugs is suspected to be highly variable potentially leading to reduced treatment effectiveness. This work aimed to develop and validate the Methotrexate Experience Questionnaire (MEQ), a tool to identify and characterize non-adherence to oral MTX. Methods MEQ development included a literature review and qualitative interviews with RA patients and physicians in the United States. A retrospective, cross-sectional study using data from Optimum Patient Care Research Database, a large primary care database of electronic medical records in the United Kingdom, was conducted to finalize the MEQ and evaluate its psychometric properties. Results Three hundred seven e-consented subjects (66% women, mean age of 65 years) completed the MEQ remotely, and were included in this analysis. Item-convergent and divergent validity were generally supportive of the construct validity of the MEQ and Cronbach’s alpha of 0.87 supported its reliability. The MEQ Total score presented statistically significant correlations of small to medium size with all selected concurrent scales, as expected; the highest correlation was obtained between the general acceptance score of ACCEPT and the MEQ Total score (0.55, p

ImportanceBefore surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines.ObjectiveTo evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery.Design, setting, and participantsRandomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France.InterventionPatients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115).Main outcomes and measuresThe primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery.ResultsOf the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes.Conclusions and relevanceAmong patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy.Trial registrationClinicalTrials.gov Identifier: NCT03374449.